Variant Analysis Release Notes

Release 3.1.20150207

This new release features access to the most extensive community database of allele frequencies, facilitated sharing, and instant access to HGMD content.

Allele Frequency Community

The Allele Frequency Community is a freely accessible “opt-in” community resource designed to facilitate sharing of anonymized, pooled allele frequency statistics among laboratories for the benefit of patients and biomedical research. Joining the community is free. Once you join, your NGS samples can be richly annotated with allele frequency information from the entire Community. Non-personally identifiable statistics from community members’ samples are used to expand the diversity of the database over time. More information about the Allele Frequency Community is available at www.allelefrequencycommunity.org

How to join the Allele Frequency Community

Ingenuity Variant Analysis users can opt their samples into the Allele Frequency Community by opting-in upon account signup,

or clicking the new “Settings” link within Variant Analysis,

then checking the “Contribute data …” checkbox.

Community Allele frequencies will be available as part of the Common Variants filter, and as a column in the variants table for users who have opted-in.

Instant Access to HGMD Content

Gain instant, direct access to HGMD content. New in this release, users are no longer required to obtain an HGMD license from BIOBASE for access to up-to-date HGMD content. Access HGMD content directly within Variant Analysis by clicking on a variants’ accession ID.

Ingenuity Admin Tool (IAT) and Group Access to Variant Analysis

The IAT tool enables account administrators to easily manage group membership without contacting QIAGEN Bioinformatics Customer Support. Users may be added or removed from your group through the Ingenuity Admin Tool (IAT) portal. To add a group (or become a group administrator) for your subscription license, please contact Customer Support and request the addition of group access to your Variant Analysis account.

Variant Analysis – New Purchasing Plans

Pay-by-sample plans have been eliminated in favor of a flexible tiered-based subscription model that simplifies budgeting and planning.

In October 2014, QIAGEN Bioinformatics introduced the Ingenuity Variant Analysis subscription plan. Customers can now purchase 12-month subscriptions of Variant Analysis with the ability to select subscription tiers that correspond to their anticipated sample throughput. Subscription tiers start at 50 samples (permitting an analysis of up to 50 samples). For more information on the new subscription tiers please refer to the “How Variant Analysis Subscriptions Work” on the Ingenuity Variant Analysis Resources page.

Please note: Activation codes and coupons for sample activation are no longer used in subscription plans.

Release 3.1.20141014

New Features:

Pre-Filtering – To optimize the loading of large cohort studies (greater than: 200 genomes or 2000 exomes) Variant Analysis now features a pre-filter step as part of the Analysis Setup Wizard. Now users can apply some of the filters available in the Filter Cascade during the pre-analysis step to optimize system resources by focusing on exonic regions, high quality variants or likely causal variants typically absent in a “normal” population. Users who are interested in disabling this feature may do so by contacting Ingenuity Customer Support.

Filtering on Copy Number Variants – Variant Analysis now accepts Copy Number Variation (CNV) information specified as a range of bases along with it’s copy number in the VCFS files. Ingenuity Variant Analysis will refer the VCF’s copy number for the variants that occur within the CNV range. This CNV value will supersede the Variant Analysis-inferred CNV value. A max CNV value of 9 is supported with values above 9 cited as 9. Variants that occur in overlapping CNV region with different CNV values will be assigned the higher CNV value.

This update to Variant Analysis currently does not support the following CNV information if provided in the VCF file:

DUP:TANDEM Tandem duplication

DEL:ME Deletion of mobile element relative to the reference

INS:ME Insertion of a mobile element relative to the reference

Splice Site Prediction – New for this release is the ability to predict the effects of single nucleotide variations (SNV) on splice sites within the Predicted Deleterious Filter window. Based on MaxEntScan the Variant Analysis algorithm will predict the following mutation event outcomes:

Exon truncation

Exon extension

Exon skipping

This feature is available within the Predicted Deleterious Filter.

Further explanation of the prediction is shown in the Details page.

HGMD Content Support – Now HGMD content will be displayed as annotations within Variant Analysis. While hyperlinks to the HGMD Pro portal will remain, the HGMD annotations are now included alongside all other available annotations for the variant. Please note, HGMD content will only be displayed if available for the variant.

HGMD Variant Filter – A new feature available within the Predicted Deleterious Filter window that limits the filtered selection to HGMD annotated variants.

Release 3.1.20140919

Quantitative Traits filter – To correlate variants with degree of severity of a phenotype, Ingenuity Variant Analysis now features a tool to find variants that may contribute to severity of an observed trait. This feature is available within the Statistical Association filter and requires the user to upload the trait(s) of interest using the upload annotations features. Additionally all samples to be filtered using this feature must have a non-null value for its trait of interest. Acceptable values for a trait’s degree of severity include Boolean or numeric. The feature currently does not accept traits with more than 2 alphanumeric values for trait severity (ex. Acceptable: “yes’, “no”; Non-acceptable: “yes, “no”, “maybe”).

Option to remove existing annotations – Allow removing of existing annotations: previously users cannot remove existing annotations. Now users can do so by using a file with the matched annotation column but with blank value for the sample.

EGFR Exon 19 deletion gain of function – Within exon 19 of EGFR gene, any variant causing in-frame deletion or insertion through nucleotide deletion, insertion or substitution will have a Gain of Function call for Inferred Activity.

Mini Findings – Fast, breaking scientific articles referencing the identified variant. These articles have yet to be deeply curated by our expert curation team are provided to the user as the latest most up-to-the-minute findings in the scientific literature with detailed curation to come soon.

Release 3.1.20140729

New Features/Fixes:

Segregation by family/kindred functionality - New for this release is the ability to segregate samples by their family relationship. This feature is available in the Genetic Analysis filter and requires an uploaded PED file to describe the familiar relationship between samples to be segregated. One may segregate families of samples by gene or by variant.

Enhanced Field Filtering – To enhance search for samples, Ingenuity Variant Analysis now automates search for samples using a one-click feature by clicking on a sample’s attribute fields that are highlighted in gray. A simple click on one of these gray-highlighted fields quickly narrows your samples list to all samples that match that field’s value. Available gray-highlighted fields may be system created fields or fields uploaded via the annotations upload feature.

Option to disable auto-recalculate for filter changes – A feature to greatly reduce time when changing multiple filter settings is the option to disable auto-recalculate. Users can now make multiple changes to the filter cascade without the system performing a recalculate step for each filter cascade change which may take several minutes. By unchecking the auto-recalculate, users can now make multiple changes to the filter cascade, and then with one click, apply all changes in one step thereby making iterative changes to the filter cascade faster.

Release 3.0.20140520

Release 3.0.20140417

New Features/Fixes:

Analysis with 200 or less whole genome samples can optionally be pre-filtered to only include intronic regions +/- 20bp flanking . This will result in faster time to results and more efficient use of resources.

Computed assessments are now based on latest draft ACMG 2014 guidelines, including frameshifts in genes implicated in diseases where loss of function is a known mechanism of action. This may cause some variants which previously had uncertain significance to now be (likely) pathogenic and pass through Predicted Deleterious filters.

HGVS nomenclature refinements.

Normalization of INDEL display across file format.

Improved sample(s) and analysis status with end date, color indicator and filtering.

Release 2.4.20140307

New Features/Fixes:

Implementation of dynamic assessment using ACMG Draft clinical assessments along with a details panel indicating the list of supporting evidence for (+) pathogenicity or against (-). For more details on how the assessment’s determination is made, please contact Ingenuity Product Support at support@ingenuity.com.

Analysis containing more than 200 whole genome sequencing (WGS) samples will automatically exclude functionally uncharacterized non-genic and deep intronic segments. This will result in faster time to results and more efficient use of resources. Users can still opt to analyze the entire genome for sample sizes greater than 200 by contacting Ingenuity Product Support.

Release 2.3.20131217

New Features/Fixes:

Mitochondrial variants from multiple mitochondrial reference sequences are now supported (and translated to RCRS coordinates), including genome annotations and findings, for new analyses.

Sample-specific Allele Fraction can be added via Edit Columns and viewed in genotype icon tooltips for new analyses which have AD and DP variant data, to see the percentage of reads with the variant allele.

Ingenuity Pathway Analysis users now get links in gene and drugs views to jump into IPA.

Father and Mother subject IDs are now shown in Analysis Overview page when pedigree information exists when analysis was run for reference.

New Position detail in the variant panel provides copyable position text and links to genome browsers (IGV and UCSC) to streamline review of raw read pileups or other local information.

Release 2.2.20131017

New Features/Fixes:

Pathways page now provides list of drugs ordered by their ability to counteract the impact of mutations on the pathway, with links to supporting literature evidence and drug view that provides summary of the compounds’ pharmacology, clinical trials, and targets.

SKAT-O algorithm (which automatically optimizes between burden test and association test) is now used by the Statistical Association filter (Case or Control option), to identify genes or pathways with an excess burden of rare variants (the p-values and optimal weights are shown in the corresponding Genes or Pathways pages).

Gene panel samples may now be purchased directly within the application.

Performance enhancements for large analyses.

Release 2.2.20130919

New Features/Fixes:

Variants that fall within ENCODE transcription factor binding sites can now be selected in the Predicted Deleterious filter.

A new “ENCODE TFBS” Regulatory Site indicates regions observed to be bound by a transcription factor (specified in the Regulators column and the Variant details view).

The Variant table search box now does exact gene symbol matches when quoted and supports dbSNP rs number search.

COSMIC identifiers can now be added to the Variant table view via Edit Columns.

The Fused to annotation now indications chromosomal breakpoint location of fusion partner.

Addition of ‘equal to’ as comparison option for the Custom Annotation filter

Release 2.0.20130402

New Features/Fixes:

Easily re-use settings from another analysis to use the same filter cascade.

Include any custom annotations such as BED file(s) uploaded in the initial analysis or inheritance pattern selection.

Tentatively assign same case and control samples when creating a new analysis.

The Legend now show the Confidence of a sample in lieu of the Call Quality. For example in variant being present in each sample based on preceding Confidence Filter is now shown by dark (confident) versus light (not) color shading of Case and Control genotype icons

The region into introns to consider for potential splice site mutations can now be increased from the canonical junctions (+/-2 nucleotides adjacent to exons) in the Predicted Deleterious filter. When enabled, intronic variants now are only counted as being in the gene by subsequent filters if they occur within this region to avoid counting overlapping genes.

Now the HGVS Transcript Variant and Protein Variant columns include the coding and protein form qualifiers (c. and p. prefixes, respectively) to make the form explicit.

A What’s New link will appears if there’s been a new product release since your last login. The Release Notes are also available from the online Help

The analysis Summary tab per-sample vertical stacked bar charts by value are now scaled by # variants (max across all samples) rather than % total variants within each sample. This better calls out visually if certain samples are skewed with many more variants than expected overall or for a particular value.

Release 2.0.20130314

New Features/Fixes:

Missense variants (majority of variants in a genome) can be selected for separately from other types of (typically more deleterious) variants in Predicted Deleterious filter

PolyPhen-2 is now available to exclude variants it predicts are not functionally benign

The gene details panel list for the Genes, Groups/Complexes, Pathways, Processes, and Diseases summary pages summarizes number of samples with variants in the gene for cases and controls as well as the inferred impact of the variants on the gene activities (loss, normal/carrier status, or gain of function).

The click on a gene in the gene details panel jumps to Variants table with the gene in the search box to quickly see the corresponding variants

Summary tab now enables per-sample bar chart view of the values to quickly identify any outliers

Exome server project data is distinguished between zero (no exomes with variant gets 0%) and no data, including in Common Variants filter.

Cytoband in Variant Details panel is hyperlinked now to UCSC genome browser which enables quick access to multiple sequence alignments and chromosome and position details.